Oxazaphosphorines belong to alkylating agents that have been widely used in routine clinical practices to treat several types of cancer from soft tissue tumor to lymphoma. Oxazaphosphorines include ifosfamide (IFO), cyclophosphamide (CPM) and trofosfamide, which have an isomeric structure containing one, two or three chloroethyl groups bound to the nitrogen atoms. As prodrugs, these compounds require a metabolic activation fulfilled by specific liver cytochrome P450 (CYP). This activation produces hydroxylated intermediates which by a ring opening mechanism liberate the active drug, namely the nitrogen mustard which displays cytotoxicity by DNA crosslinks. The main activation pathway of IFO is carried out by CYP3A4 and involves an oxidation reaction on the C-4 carbon atom, leading to 4-hydroxy-ifosfamide (4-HO-IFO). 4-HO-IFO gives rise to the alkylating mustard concomitantly with acrolein through tautomeric equilibrium and retro-Michael process. Acrolein is responsible for the urological toxicity characterized by hemorrhagic cystitis. Acrolein-related toxicity can be attenuated by co-administration of sodium mercaptoethanesulfonate. In addition, oxazaphosphorines may also cause neurotoxicity and nephrotoxicity due to the release of chloroacetaldehyde, a metabolite produced by oxidation of the side chains of the molecules via the action of cytochrome, in particular CYP2B6 (see FIG. 5).
To circumvent these toxicities, pharmacomodulation of oxazaphosphorines has been investigated. Chemical oxidation of the C-4 carbon center has been proposed in order to provide pre-activated analogues able to release the alkylating mustards without undergoing metabolization by cytochrome P450. Many derivatives have already been prepared such as 4-methoxy derivatives (Paci et al., 2001, Bioorg Med Chem Lett, 11, 1347-1349) but most of them were either found too unstable for further development or had no advantage over the use of IFO.
WO2012/076824 discloses ifosfamide derivatives SQ-IFO and SQ-thio-IFO, which comprises a squalenoyl radical at C-4 carbon. These compounds were shown to display cytotoxicity on several cancerous cells and to be able to self-organize into nanoparticles thanks to its long hydrophobic tail. However, squalenoyl derivatives are not easily accessible and their preparation may require the use of toxic reagents, which are generally precluded from the synthesis of active ingredients to be used in medicine.
There is still a need for new derivatives of oxazaphosphorines for the treatment of cancers.